Process for preparation of 2{60 ,3{60 -epithiosteroid

ABSTRACT

A process for the preparation of the hormonal 2 Alpha ,3 Alpha epithio-5 Alpha -steroid of estrane, androstane or the pregnane series which comprises reaction of the corresponding Delta 2-5 Alpha -steroid with thiocyanogen halide, followed by treatment of the products under basic conditions, some of the products thereof and pharmaceutical compositions containing the products thereof.

United States Patent Komeno et al.

[ June 27, 1972 PROCESS FOR PREPARATION OF 2a,3a-EPITHIOSTEROID Taichiro Komeno, Osaka; llikozo Iwakura, Amagasaki, both of Japan Assignee: Shionogi & Co., Ltd., Osaka, Japan Filed: April 30, 1970 Appl. No.: 33,522

Inventors:

Foreign Application Priority Data May 8, 1969 Japan ..44/35340 U.S. Cl ..260/239.5, 260/397.4, 260/397.45,

260/397.5, 260/999 Int. Cl ..C07c 167/36 Field of Search Machine Searched Steroids [56] References Cited A process for the preparation of the hormonal 2a,3a-epithio- Sa-steroid of estrane, androstane or the pregnane series which comprises reaction of the corresponding A -5a-steroid with thiocyanogen halide, followed by treatment of the products under basic conditions, some of the products thereof and pharmaceutical compositions containing the products thereof 4 Claims, No Drawings PROCESS FOR PREPARATION OF 201,3!- EPITHIOSTEROID The present invention relates to 2a,3a-epithiosteroids. More particularly, it relates to a novel process for the preparation of 2a,3a-epithiosteroids, products thereof and pharmaceutical preparations containing the products of this invention.

The novel process of the present invention for the preparation of 2a,3a-epithiosteroids comprises the reaction of a thiocyanogen halide with a A -5a-steroid of the estrane, androstane or pregnane series to afford (2 or 3 )a-thiocyanato-( 3 or 2)3-halo-5a-ster0ids or its derivatives, followed by treatment of the product under basic conditions.

The known process for preparation of 2a,3a-epithio-Sa-steroids involves a process starting from a 3-oxo-5a-steroid compound prepared from the corresponding 3-hydroxy-compound by oxidation, in which the starting material is halogenated and reduced to its 3-oxo group to give a halohydrin, and the latter is treated with a base to afford an epoxide, the epoxide is then treated with thiocyanic acid to give thiocyanatohydrin, which is treated with a base to afford the desired compound; and a process starting from a 3-oxo-5a -steroid compound, in which the starting material is halogenated, the introduced halogen atom is replaced'with thiocyanato group, the x0 group is reduced to give thiocyanatohydrin, and the latter is treated with a base to afford desired compound. Total yields of both of the processes are lower because of e.g. multiplied unit processes, possible side reaction causing lower yield such as halogenation at undesired position, and so on in the former process, and e.g. lower yield of replacement reaction of halogen atoms with thiocyanato group and undesired halogenation in the halogenation step in the latter process.

The reaction of the present invention is represented e.g. by the following reaction scheme for ring A of the steroid wherein X is a halogen atom and R is a methyl group or hydrogen atom. in the reaction of the first step, as the thiocyanato cation attacks the double bond mainly from a-side, the thiocyanato group of the products occupies mainly at 04- positions, and as the result, the products of the second step have mainly epithio groups of zit-configuration.

The process of the present invention comprises as the first step reacting a thiocyanogen halide on the A -steroid; and as the second step reacting base on the products of the first step.

As for the starting materials of the present invention, the A steroid of estrane, androstane or pregnane series, preparable for example by dehydration of the corresponding 3-hydroxy compounds, are utilized. They can possess a conventional inert substituent, e.g. a lower hydrocarbon group hydroxyl group, acyloxy group, alkoxy group, oxo group, alkylenedioxy group, halogen atom, unsaturated bond, nitrogen or sulfur functions and the like at any position in the steroid nucleus in addition to the double bond at position 2(3). Representatives of these materials are as follows 5a-androst-2-en- 1 73-01,

1 7a-methyl-Sa-androst-Z-en-173-01,

l7a-ethyl-5a-androst-Z-en-173-01,

l 7a-propyl-5a-andr0st-2-en- 173-01,

17a-ethynyl-Sa-androst-Z-en-173-01,

la-methyl-5a-androst-2-en-173-01, 2-methyl-Sa-androst-Z-en-173-01,

3-methyl-Sa-androst-Z-en- 1 73-01,

7a-methyl-5a-androst-2-en-173-01,

83-methyl-5a-androst-2-en-173-01,

l 8-methyl-5a-androst-2-en-173-01,

70:17a-dimethyl-Sa-androst-Z-en-173-01,

base

5a-androst-2-ene- 63, l 73-diol,

5a-androst-2-ene-7a, 1 73-diol, l7a-methyl-5a-androst-2-ene-63, l 73-diol, 17a-methyl-5a-androst-2-ene-7a, 1 73 -diol, 5a-androsta-2,6(7)-dien- 173-01,

5a-androsta-- 2,9( l 1 )-dien- I 73-01,

1 7-methylene-Sa-androst-Z-en- 1 73-01, 17a-methyl-5a-androsta-2 ,6( 7 )-dien- 1 73-01, l7a-methyl-5a-androsta-2,9( l l )-dien- 1 73-01, l7a-ethyl-5a-androsta-2,9( l l )-dien-l 73-01, 5a-estr-2-en- 1 73-01, l7a-methyl-5a-estr-2-ene-173-01, 5a-pregn-2-en-20-one, 9a-fluoro-5a-pregn-2-ene-20-one,

l 7a-hydroxy-5a-pregn-2-en-20-one,

1 6a, 1 7a-dihydroxy-5a-pregn-2-en-20-one,

l 7a-hydroxy-5a-pregn-2-enel l ,20-dione,

1 704,2 1 -dihydroxy-5a-pregn-2-en-20-one,

9a-fluoro- 1 711,2 1-dihydroxy-5a-pregn-2-en-20-one, 63-fluoro- 1 701,2 1 -dihydroxy-5a-pregn-2-ene-20-one,

' 63-methyl-9a-fluoro- 1 701,2 l-dihydroxy-5a-pregn-2-en-2 0- one, and their esters, ethers oxygenated compounds especially in the case of androstan- 1 73-01 derivatives, the corresponding 1 7-oxo derivatives.

The ester group in the starting materials may be an organic or inorganic acylate such as alkanoate, e.g. acetate, propionate, enanthate, dodecanoate, etc.; alicyclic acylates, e.g. cyclopropylcarboxylate, adamantoate, etc.; unsaturated acylate, e.g. ethynylacetate, undecenoate, etc.; aromatic acylate, e.g. benzoate, substituted benzoate, etc.; substituted alkanoates, e.g. phenoxyacetate, chloroacetate, phenylpropionate, etc,; sulfonates, e.g. methanesulfonate, ethanesulfonate, benzenesulfonate, toluene-p-sulfonate, etc.; or inorganic acylates, e.g. carbonate, phosphate, sulfate, etc.; and ethers or acetals may be ether, e.g. l-alkoxycycloalkyl ether, cycloalkenyl ether, tetrahydropyranyl ether, methyl ether, etc.; or

acetal, e.g. dimethyl ketal, methylene ketal, ethylene ketal,

etc. The reagent of the process of the present invention, a thiocyanogen halide is thiocyanogen chloride, thiocyanogen bromide or the like. These are conveniently prepared by the methods described eg. in Journal of the Chemical Society, page 318, 1960, for example by the reaction of alkali thiocyanate and halogen or by the reaction of thiocyanogen and halogen.

The first step of the process of the present invention is carried out by reacting a thiocyanogen halide on the said starting material. The reaction of this step is carried out by bringing the starting material into contact with the thiocyanogen halide. This reaction weakly exothermic and may be carried out at room temperature or at a lower temperature. Five to a hundred mole equivalents of the reagent givepreferable results. The reaction medium can be stirred or kept under inert gas. The reaction can be carried out in a solvent. The solvents used in this step may be hydrocarbons, e.g. petroleum ether, heptane, toluene, benzene, etc.; halogenated hydrocarbons, e.g. carbon tetrachloride, chloroform, methylene chloride, dichloroethane, chlorobenzene, etc,; ethers, e.g. diethyl ether, tetrahydrofuran, dioxane, etc.; esters, e.g. ethyl acetate, butyl acetate, etc.; alcohols, e.g. menthanol, ethanol, butanol, etc.; organic acids, e.g. acetic acid, propionic acid, etc.; organic bases, e.g. pyridine, collidine, etc.; and other solvents, e.g. dimethylformamide, nitrobenzene, acetonitril, water, etc., or mixtures thereof. Sometimes preferable results are obtained when the reaction medium is anhydrous. When the reaction of this step was carried out in acetic acid, the reaction proceeded very rapidly. After 30 minutes, the mixture began to show slow secondary changes and a shorter reaction period was preferable. When the solvent can form an anion, e.g. acetate ion, the anion from the solvent instead of reacting with the halogen ion, reacts with the thiocyanato carbonium ion to some extent and affords products such as acetylated thiocyanatohydrins which may be converted to the same 204,30:- epithio compound by reaction of the second step. If desired, the products of the first step are subjected to the reaction of the second step without purification or separation of individual products. This procedure saves loss of products and troubles caused by isolation and results in higher total yield. The reaction of the first step is an addition reaction forming mainly a trans-diaxial substituent. Under'some conditions, a transdiequatorial substituent is formed to some extent. Both of. the trans-diaxial and diequatorial compounds of the products of the first step give the same product by the process of the second step. 7

- In the secondstep of the process of the present invention, the products of the first step are treated under basic conditions. The basic condition for this purpose is obtained with a base ranging from weak base, e.g. alumina, to a strong base. Representatives of these involve a weak base, e.g. alumina, alkali metal hydrogen carbonate, alkaline earth, metal carbonate, ammonia, alkylamines, and a strongbase, e.g. alkali metal carbonates, alkali metal hydroxide, tert-ammonium hydroxide, etc., or ion-exchange resins of various basicity. They are utilizedin solvents, e.g. hydrocarbons, halogenated hydrocarbons, ethers, esters, alcohols, organic bases and other organic solvents, water etc., or their mixtures. Generally, the reaction of this step is carried out at room temperature or at elevated temperature.

The products of thefirst step and the second step are isolated and purified in conventional manner, e.g. by dilution, filtration, extraction, washing, drying, concentration, recrystallization, chromatography, absorption, elution, etc., or combinations thereof. If required, the products of the first step may be subjected to reaction of the second step without further purification. Each of them can be esterified, ketalated or etherified for convenience of purification and utilization.

Under somereaction conditions, hydrolysis of some groups such as esters, ketals, ethers or the like occurs. The compounds of desired structure can be recovered by subjecting the products to the above reactions.

The product of the process of the present invention is the 2a,3a-epithi0-5a-steroid of the estrane, androstane or pregnane series. These compounds can possess a conventional substituent, e.g. lower hydrocarbon group, hydroxyl group, acyloxy group, alkoxy group, oxo group, alkylenedioxy group, halogen atom, unsaturated bond, nitrogen or sulfurfunctions and the like at any position on the steroid nucleus in addition to the 2a,3a-epithio group. Representative of these compounds are:

2a,3a-epithio-5a-androstan-1713-01, 2a,3a-epithiol 7a-methyl-5a-androstanl 7B-ol, 2a,3a'epithiol 7a-ethyl-5a-androstanl 7B-ol, 2a,3a-epithio l 7a-propyl-5a-androstan-' l 7B-ol, 2a,3a-epithiol 7a-ethynyl-5a-androstan- 1 713-01, 2a,3a-epithiola-methyl-Sa-androstan-1713-01, 2a,3a-epithio-Zfl-methyl-Sa-androstan- 1 73-01, 2a,3a-epithio-3B-methyl-5a-androstan- 1 75-0], 2a,3a-epithio-7a-methyl-Sa-androstan-l73-01, 2a,3a-epithio-8B-methyl-5a-androstan- 1 713-01, 2a,3a-epithiol 8-methyl-5a-androstan-173-0], 2a,3a-epit hio-7a, l 7a-dimethyl-5a-androstanl 7B-ol, 2a,304-epithio-5a-androstane-6fl, l 7B-diol, 2a,3a-epithio-5a-androstane-7a, l 7B-diol,. 2:1,3a-epithiol 7a-methyl-Sa-androstane-GB, l 7B-diol, 2a,3a-epithiol 7a-methyl-5a-androstane-7a, l 7fl-diol, I 2a,3a-epithio-5a-androst-6( 7 )-en- 1 7B-ol, 2a,3a-epithio-5a-androst-9( l l )-en-l7B-ol, 2a,3a-epithio-l7-methylene-Sa-androstan-173-0], 2a,3a-epithio-l7a-methyl-5aandrost-6(7)-en-l7B-ol, I 2a,3a-epithiol 7a-methyl-5a-androst-9( l l )-ene- 17,8-ol, 2a,3u-epithiol 7a-ethyl-5a-androst-9( l 1 )-en- 1 73-01, 2a,3a-epithio-5a-estranl 7,8-ol, 2a,3a-epithio-l7a-methyl-5a-estran-l713-0], 2a,3a-epithio-Sa-pregnan-ZO-one, 2a,3a-epithio-9a-fluoro-Sa-pregnan-ZO-one, 2a,3a-epit hio- I 7a-hydroxy-5a-pregnan-20-one, 2a,3a-epithio- 1 6a, 1 7a-dihydroxy-Sa-pregnan-ZO-one, 2a,3a-epithio-l 7a-hydroxy-5a-pregneane-l 1,20-dione, 2a,3a-epithio- 1 711,2 1 -dihydroxy-a-pregnan-20-one,

2a,3a-epithio-9a-fluorol 7a,2 l -dihydroxy-5a-pregnan-20- one, 2a,3a-epithio-6B-fluoro-l 701,2 1 -dihydroxy-5a-pregnan-20- one, v 2a,3a-epithio-GB-methyl-Qa-fluoro-l 701,2 1 -dihydroxy-5 apregnan-ZO-one,

and their esters, ethers, oxygenated compounds especially in the case of androstanl 7B-ol derivatives, the corresponding 17-oxo derivatives. The esters, ethers, acetals and the like of the products of this invention may be those cited in the explanation of the starting materials of the present invention. I

The compounds prepared by the process of the present invention are useful as the active ingredient in medicine of pharmaceutical, veterinary or poultry use for the medical activities such as estrogenic activity, anti-estrogenic activity, myogenic activity, androgenic activity, antiinflammatory activity, antifertility efiect, anti-microbial activity, pituitary gonadotrophin inhibiting activity, wound healing activity, lipid shifting activity, uterotropic activity, anti-uterotropic activity, antimammary growth activity, anti-progestational activity,- diuretic activity, and related activities. Further, the process of the present invention is superior to the known methods from the view point of the overall yield from the same starting material. Moreover, the process of the present invention is three steps from easily available 3-hydroxy compounds, in contrast to more than six steps of the known methods. Hence, the process of the present invention is of practical value. t

The novel compounds of the present invention are the compounds selected from the group consisting of: 2a,3q-epithio-Sa-androstane-fi, l 7B-diol, 2oz,3a-epithio-Sa-androstane-7a, l 7/3-diol, 2a,3a-epithio-5a-androst-9( 1 1 )-en- 1 73-01 and their v 17a-hydrocarbon substituted compounds, and 2a,3a-epithiol 7a-hydroxy-5a-pregnane-l l ,20-dione, and

esters thereof. These compounds are useful for their various hormonic activities e.g. anti-uterotropic activity, lipid shifting activity; es-

trogenic activity, anti-estrogenic activity, myogenic activity,

androgenic activity, anti-mammary growth activity, anti-implantational activity, antiinflammatory activity, and the like. For example, 2a,3a-epithio-5a-androstane-6B,17B-diol shows strong anti-uterotropic and lipid shifting activities when administered to a rat; 2a,3a -epithio-5a-androstane-7a,l7B-diol shows a 257 percent increase of value of vaginal TTC reduction at a dose of 3 mg per mouse, and a 64 percent inhibition of estrogenic response when tested by the vaginal 'ITC reduction method at a dose of 0.3 mg per mouse, which value. is larger than that of 2a,3a-epithio-5a-androstan-l7B-ol; 2a,3aepithio-5a-androst-9( l l)-ene-l7B-ol shows 1.7 times myogenic activity and 0.4-0.5 times androgenic activity than testosterone propionate at a dose of 0.5-2.0 mg per rat, 63 percent inhibition of mammary growth at a dose of 0.05 mg per mouse, 65 percent inhibition of effect of estradiol when tested by a vaginal TTC reduction method at a dose of 0.03 mg per mouse, 100 percent delay or inhibition of implantation at a dose of 1.5 mg per rat, and 305 percent of estrogenic effect at a dose of 3 mg per mouse; 2a,3a-epithio-l7a-hydroxy- Sa-pregnane-l 1,20-dione acetate showed 19 percent reduction of volume of exudation at a dose of 1 mg per rat. These effects show that the compounds are useful as medicaments for treatment of various disorders, insufficiencies or control of physiological functions in warm blooded animals for human, veterinary or poultry purposes at a dosage of 0.00l500 mg per kilogram of body weight. These compounds are suitable for enteral or parenteral administration in.various conventional forms of liquid or solid preparations as a mixture of the effective doses of the compounds and as a pharmaceutically acceptable carrier.

, The following examples are given to show the embodiment of the present invention but are not intended to limit the scope thereof. Abbreviations are those of conventional meanings.

EXAMPLE 1 1. To a solution of 528 mg of chlorine in 50 ml of glacial acetic acid is added 800 mg of potassium thiocyanate, and the mixture is stirred at room temperature for 20 minutes. To the solution is added a solution of 200 mg of Sa-androst-Z-en- 173-01 in ml of glacial acetic acid, and the mixture is stirred at room temperature for 1 hour 40 minutes. The reaction mixture is poured onto iced water and extracted with methylene chloride. The extract solution is washed with water, 10 percent aqueous solution of sodium carbonate and water, respectively, dried over anhydrous sodium sulfate and evaporated to dryness. Separation of 285 mg of the residue by thin-layer chromatography over silica gel gives 133 mg of 2B-chloro-3athiocyanato-Sa-androstan-l7B-ol (m.p. l06108 C. Yield: 49.6 percent.[a 1,, +45.3 1 08 (c 1.007, chloroform)) from the fraction of higher Rf value, 27 mg of 3fi-chloro-2athiocyanato-Saz-androstan-l7B-ol(IR: ,5 5 3586,2170 cm".

Yield: 10.06 percent from the fraction of median Rf value and 23 mg of 2B-acetyloxy-3a-thiocyanato-5a-androstan-l7B-ol (Yield: 8.42 percent. IR: 110E613 35 2170, 740 m from max. the fraction of lower Rf value.

2. To a solution of 248 mg of ZB-chloro-3a-thiocyanato-5aandrostan-l7B-ol in a mixture of 2.5 ml of dioxane and 2.5 ml of methanol is added 250 mg of potassium carbonate in 1 ml of water, and the mixture is stirred at room temperature for 5.5 hours. The reaction mixture is diluted with water, and the separated crystals are washed with water. The crystals are dissolved in methylene chloride, washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. Separation of 207 mg of the residue by thin-layer chromatography gives 153 mg of 2a,3a-epithio-5a-androstan-173-0] and 22 mg of 5a-androst-2-en-l7/3-ol.

3. To a solution of 44 mg of 3B-chloro-Za-thiocyanato-Sw androstan-l7,B-ol in a mixture of 0.5 ml of dioxane and 0.5 ml of methanol is added a solution of 50 mg of potassium carbonate in 0.2 ml of water, and the mixture is stirred at room temperature for 48 hours minutes. The reactiOn mixture is diluted with water, and extracted with methylene chloride. The extract solution is washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. Separation of 39 mg of the residue by thin-layer chromatography over silica gel affords 2.5 mg of 5a-androst-2-en-27B-ol and 14 mg of 2oz,3a-epithio-5a-androstan-l 7B-ol accompanied with 4 mg of the starting material.

4. To a solution of 23 mg of ZB-acetyloxy-3a-thiocyanato- Sa-androstanl 7,8-01 in a mixture of 0.5 ml of dioxane and 0.5 ml of methanol is added a solution of 50 mg of potassium carbonate in 0.2 ml of water, and the mixture is stirred at room temperature for 3 hours. The reaction mixture is diluted with water and extracted with methylene chloride. The extract solution is washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. Purification of 19 mg of the residue by thin-layer chromatography affords 12.5 mg of 2a,3a-epithio-5a-androstan-17B-ol.

EXAMPLE 2 To a solution of 1.4 g of chlorine in 50 ml of chloroform is added 2.4 g of dirhodane in 100 ml of chloroform, and the mixture is stirred at room temperature for 30 minutes. To the solution is added 2.88 g of l7a-methyl-5a-androst-2-en-17B- ol in 10 ml of chloroform and the mixture is stirred at room temperature for 1 hour. The reaction mixture is washed with iced water, 10 percent aqueous solution of sodium carbonate and water, respectively, dried over sodium sulfate and evaporated to dryness under reduced pressure. To a solution of 3.32 g of the residue in a mixture of 30 ml of methanol and 30 ml of dioxane is added a solution of l g of potassium hydroxide in 5 ml of water, and the mixture is stirred for 10 hours at room temperature. The reaction mixture is diluted with water and extracted with methylene chloride. The extract solution is washed with water, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. Purification of 2.67 g of the residue by thin-layer chromatography over silica gel affords 2.4 g of 2a,3a-epithio-l7amethyl-5a-androstan-l7B-ol, m.p. l68l69 C. Yield: 75.0 percent.

EXAMPLE 3 According to a similar procedure to that of Example 2, lamethyl-Sa-androst-Z-en-173-01 is reacted with thiocyanogen chloride in glacial acetic acid for 1 hour, Followed by treatment of the product with potassium hydroxide in a mixture of methanol and water for 1 hour to afford 2a,3a-epithio-lamethyl-Sa-androstan-17B-ol, m.p. l24l 26 C, in 73 percent yield; 7a-methyl-Sa-androst-Z-en-17B-ol is reacted with thiocyanogen chloride in glacial acetic acid for 1 hour, followed by treatment with sodium carbonate in a mixture of ethanol and dioxane to afford 2a,3a-epithio-7a-methyl-5a-androstan- 17,8-ol, m.p. l40l43 C, in 67 percent yield.

EXAMPLE 4 To a solution of 1.917 g of chlorine in ml of glacial acetic acid is added 3.0 g of potassium thiocyanate, and the mixture is stirred for 10 minutes at room temperature. To a solution is added a suspension of 724 mg of 7a, 1 7B-dihydroxy-5a-androst-2-ene in 40 ml of glacial acetic acid, and the mixture is stirred at room temperature for l hour. The reac tion mixture is poured onto iced water and extracted with methylene chloride. The extract solution is washed successively with water, 10 percent aqueous solution of sodium carbonate and water, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. To a solution of 929 mg of the residue in a mixture of 10 ml of dioxane and 10 ml of methanol is added 1 g of potassium carbonate in 4 ml of water, and the mixture is stirred at room temperature for 5 hours and kept at room temperature for 12 hours. The extract solution is washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure to dryness. Purification of 797 mg of the residue by thin-layer chromatography over silica gel afiords 548 mg of 2a,3a-epithio-5a-androstane-7a, l 7B-diol, m.p. l64166 C. [01],, 7.8 i 0.5 (c 0.994, chloroform). Yield: 68.0 percent.

EXAMPLE 5 According to a similar procedure to that of Example 4, 5aandrost-Z-ene-GB,17,8-diol is reacted with thiocyanogen chloride in chloroform for 0.5 hour, followed by treatment of the product with potassium carbonate in a mixture of dioxane and methanol for 15 hours to afford 2a,3a-epithio-5a-androstane-6B,l7B-diol, m.p. l80-l82 C, in 70 percent yield; 5a-estr-2-en-l7B-ol is reacted with thiocyanogen chloride in chloroform for 1 hour, followed by treatment of the product with potassium carbonate in a mixture of dioxane and ethanol for 5 hours to afford 2a,3a-epithio-5a-estran-173-01, m.p. ll5-ll7 C, in 76 percent yield; and 5a-androsta-2,9(l 1)- dien-l7B-ol is reacted with thiocyanogen chloride in methylene chloride for 0.5 hour, followed by treatment of the product with potassium carbonate in a mixture of dioxane and methanol for 4 hours to afford 2a,3a-epithio-5a-androst-9 (ll)-en-l7B-ol, m.p. l26l28 C, in 40 percent yield (acetate, m.p. l37-l39 C).

EXAMPLE 6 1. To a solution of 1.94 g of chlorine in ml of glacial acetic acid is added 3.0 g of potassium thiocyanate, and the mixture is stirred at room temperature for 10 minutes. To the solution is added 1.000 g of l7a-acetyloxy-l1,20-dioxo-5apregn-Z-ene as a suspension in 50 ml of glacial acetic acid and the mixture is stirred at room temperature for 1 hour. The reaction mixture is poured onto iced water and extracted with methylene chloride. The extract solution is washed successively with water, 10 percent aqueous solution of sodium carevaporated to dryness under reduced pressure. Separation of I l .473 g of the residue by thin-layer chromatography gives 677 mg of 2fi-chloro-3a-thiocyanato-l7a-acetyloxy-11,20-dioxo- Sd-pregnane (m.p. 207-209 C. [01],, 52.4 0.9 (c 1.019, chloroform). 1R: 4,539 2143, 1738, 1710, 1246 cm) from fraction of higher Rf value and 357 mg of 23,170:- diacetyloxy-3a-thiocyanato-l 1,20-dioxo-5a-pregnane (m.p. 227230 C. 63.2 i 1 1 (c 0.996, chloroform). 1R: .r-figff 2144, 173 l 1700, 1263 cm") from the fraction of lower Rf value.

2. To a solution of 318 mg of 2B-chloro-3a-thiocyanatol 1,20-dioxo-l7a-acetyloxy-5a-pregnane in a mixture of 5 ml of dioxane and 5 ml of methanol is added a solution of 300 mg of potassium carbonate in 2 ml of water, and the mixture is stirred for 4 hours at room temperature. The reaction mixture is diluted with iced water and extracted with methylene chloride. The extract solution is washed with water, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. Separation of the residue by thin-layer chromatography over silica gel affords 206 mg of 201,301- epithio-l l ,20-dioxol 7a-acetyloxy-5a-pregnane (m.p. 167-l 69 C. [a],, 37.1:O.8(c=0.973, chloroform). IR:

V5321 2, 1709, 1245 cm") from fraction of higher Rf value and 46 mg of 2a,3a-epithio-l l,20-dioxo-17a-hydroxy- Sa-pregnane (m.p. l83-185 C. [a] 39.3 0.8 (c 0.971, chloroform). 1R: vfif f 3570, 3516, 1700 cm") from fraction of lower Rf value, accompanied with 2 -ene compound. 3. To a solution of 254 mg of 2fi,l7a-diacetyloxy-3athiocyanato-l 1,20-dioxo-5a-pregnane in a mixture of 5 ml of dioxane and 5 ml of methanol is added a solution of 300 mg of potassium carbonate in 2 ml of water, and the mixture is stirred at room temperature for 3.5 hours. The reaction mixture is diluted with iced water and extracted with methylene chloride. The extract solution is washed with water, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. Separation of the residue by thin-layer chromatography affords 105 mg of 2a,3a-epithi0-l7aacetyloxy-l1,20-dioxo-5a-pregnane, m.p. l67-169 C, and 36 mg of 2a,3a-epithio-l7a-hydroxy-l 1,20-dioxo-5a pregnane, m.p. l83-l 85 C.

EXAMPLE 7 To a solution of 1.5 g' of chlorine in 80 m1 of glacial acetic acid is added 2.5 g of potassium thiocyanate, and the mixture is stirred for 10 minutes at room temperature. To the solution is added a suspension of 1.50 g of 5a-pregn-2-ene-20-one in 20 ml of glacial acetic acid, and the mixture is stirred at room temperature for 1 hour. The reaction mixture is poured onto iced water and extracted with methylene chloride. The extract solution is washed with water, 10 percent aqueous solution of sodium carbonate and water, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. To a solution of 1.3 g of the residue in a mixture of 20 ml of dioxane and 20 ml of methanol is added 0.9 g of sodium carbonate in 4.5 ml of water and the mixture is stirred at room temperature for 6 hours. The reaction mixture is diluted with water and extracted with methylene chloride. The extract solution is washed with water, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. Purification of 1.21 g of the residue by thin-layer chromatography over silica gel and recrystallization from acetone and hexane affords l .14 g of 2a,3a-epithio-Sa-pregnan-ZO-one, m.p. -l 62 C/193Bl97 C. Yield: 69 percent.

EXAMPLE 8' According to a similar procedure to that of Example 7, 17aacetyloxy-5a-pregn-2-en-20-one is reacted with thiocyanogen chloride in glacial acetic acid for 1 hour, followed by treatment of the product with potassium carbonate in a mixture of methanol and dioxane for 12 hours to afford 2a,3a-epithio- 17a-acet lox -5are nan-20-on percent yiel lya-h ydroxy-2l-gce t y oxf fiii-l regi igan e 11,20-dione is treated with thiocyanogen chloride in glacial acetic acid for 1.5 hours, followed by treatment of the product with sodium carbonate in a mixture of methanol and dioxane for 6 hours to afford 2a,3a-epithio-2l-acetyloxy-l7a-hydroxy-Spr-pregnane-l 1,20-dione, m.p. l46l47 C and 201,301- epithio-21,l7a-dihydroxy-Sa-pregnane-l l ,ZO-dione, m.p. l52154 C, in 73 percent yield.

What we claim is:

1. A process for preparation of 2a,3a-epithio-5a-steroid of the estrane, androstane or pregnane series which comprises reacting a N-Sa-steroid with a thiocyanogen halide, followed by treatment of the product with a basic medium.

2. A process claimed in claim 1, wherein the thiocyanogen halide is thiocyanogen chloride.

3. A process claimed in claim 1, wherein the thiocyanogen halide utilized is five to a hundred mole equivalents of thiocyanogen chloride.

4. A process claimed in claim 1, wherein the basic condition is obtained with an alkali metal carbonate or hydroxide. 

2. A process claimed in claim 1, wherein the thiocyanogen halide is thiocyanogen chloride.
 3. A process claimed in claim 1, wherein the thiocyanogen halide utilized is five to a hundred mole equivalents of thiocyanogen chloride.
 4. A process claimed in claim 1, wherein the basic condition is obtained with an alkali metal carbonate or hydroxide. 